Clinical trialPhase 3Lymphoma

Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial

Lancet · 2022184 patients (92 in each group)

Kamdar M, Solomon SR, Arnason J, et al. Lancet. 2022. 399:2294-2308

A newer report of this study has been published: Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study (2025)

Study type: Clinical trial
Study name: TRANSFORM
Phase: Phase 3
Design: Randomised (1:1), open-label, global trial at 47 centres (US, Europe, Japan); prespecified interim analysis
Sample size: 184 patients (92 in each group)
Source: Lancet · 2022
Trial registration: NCT03575351

In plain words

This study, like ZUMA-7, showed that for large B-cell lymphoma that has not responded to the first treatment or has come back early, CAR-T therapy works better than the older approach of chemotherapy and a transplant. Lisocabtagene maraleucel caused fewer severe side effects (severe fever and drop in blood pressure, or severe confusion) than some other CAR-T products, but long-lasting low blood counts were common with it.

Key results

10.1 vs 2.3 months

Median event-free survival

Stratified HR 0.35 (95% CI 0.23 to 0.53); one-sided p<0.0001; median follow-up 6.2 months

1% / 4%

Grade 3 CRS / neurological event

In the liso-cel group; no grade 4 or 5 events

Drugs in this study:Carboplatin (Paraplatin)Cisplatin (Platinol)Cyclophosphamide (Endoxan)Gemcitabine (Gemzar)Rituximab (Rituxan/MabThera)

Dose and schedule cards

Second-line CAR T-cell therapy: axicabtagene ciloleucel (ZUMA-7) or lisocabtagene maraleucel (TRANSFORM)

Large B-cell lymphoma refractory to first-line treatment or relapsing within 12 months of it (candidates for intensive therapy)Cycle length: Single doseOn the page “Lymphoma” · Treatment regimens and dosing: relapsed or refractory DLBCL, eligible for transplantation or CAR T-cell therapy

Large B-cell lymphoma refractory to first-line treatment or relapsing within 12 months of it (candidates for intensive therapy)

Drug	Dose	Route	Schedule
Axi-cel: lymphodepletion
Cyclophosphamide	500 mg/m²	IV	Days −5, −4 and −3 before infusion
Fludarabine	30 mg/m²	IV	Days −5, −4 and −3 before infusion
Axi-cel
Axicabtagene ciloleucel	2 × 10⁶ CAR-positive viable T cells/kg (maximum 2 × 10⁸ cells)	IV	Once, Day 0
Liso-cel: lymphodepletion
Fludarabine	30 mg/m² daily	IV	3 days
Cyclophosphamide	300 mg/m² daily	IV	3 days
Liso-cel
Lisocabtagene maraleucel	90 to 110 × 10⁶ CAR-positive viable T cells	IV	Once, 2 to 7 days after completion of lymphodepletion

Cycle length: Single dose
Duration: One-time infusion

Doses from the FDA labels for YESCARTA and BREYANZI. Before infusion, acetaminophen and an H1 antihistamine; tocilizumab and emergency equipment must be available; the patient should stay near the treatment centre for at least 2 weeks after axi-cel infusion. In ZUMA-7, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21% of patients. In renal impairment, adjust the fludarabine and cyclophosphamide doses according to the labels of these drugs.

On the page “Lymphoma” · Treatment regimens and dosing: relapsed or refractory DLBCL, eligible for transplantation or CAR T-cell therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Lisocabtagene maraleucel (liso-cel)

Lymphodepleting chemotherapy with fludarabine 30 mg/m²/day and cyclophosphamide 300 mg/m²/day given together for 3 days, then 2 to 7 days later a single IV infusion of lisocabtagene maraleucel at a dose of 100 × 10⁶ CAR-positive T cells.

2Standard of care

Three cycles of IV salvage chemoimmunotherapy, followed by high-dose chemotherapy and autologous transplantation in responders:

R-DHAP: rituximab 375 mg/m² on day 1, dexamethasone 40 mg on days 1 to 4, two infusions of cytarabine 2000 mg/m² on day 2 and cisplatin 100 mg/m² on day 1;
R-ICE: rituximab 375 mg/m² on day 1, ifosfamide 5000 mg/m² on day 2, etoposide 100 mg/m² on days 1 to 3 and carboplatin AUC 5 (maximum 800 mg) on day 2;
R-GDP: rituximab 375 mg/m² on day 1, dexamethasone 40 mg on days 1 to 4, gemcitabine 1000 mg/m² on days 1 and 8 and cisplatin 75 mg/m² on day 1.

Source of the regimen details: Abstract of the paper (Lancet 2022) for the liso-cel dose and standard regimens; FDA label for BREYANZI (Clinical Studies section, TRANSFORM) for the lymphodepleting regimen

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults aged 18 to 75 years with large B-cell lymphoma that was primary refractory or relapsed within 12 months of first-line therapy, with ECOG performance status 0 or 1, PET-positive disease and eligibility for autologous transplantation.

Endpoints

Primary outcome: event-free survival assessed by an independent review committee per the Lugano 2014 criteria.

Key secondary outcomes: complete response, progression-free survival and overall survival.

Safety and side effects

The most common grade 3 or higher adverse events (liso-cel versus standard of care): neutropenia 80% versus 51%, anaemia 49% versus 49%, thrombocytopenia 49% versus 64% and prolonged cytopenia 43% versus 3%. Grade 3 cytokine release syndrome in 1% and grade 3 neurological events in 4% of the liso-cel group, with no grade 4 or 5 events. Serious adverse events 48% in each group. No treatment-related deaths occurred in the liso-cel group.

Clinical significance and place in guidelines

Based on this study, in June 2022 the FDA approved lisocabtagene maraleucel (Breyanzi) for second-line treatment of large B-cell lymphoma that is primary refractory or relapsed within 12 months. Together with ZUMA-7, this study made CAR-T the standard second-line treatment in this high-risk group.

Limitations

This report is an interim analysis with very short follow-up (median 6.2 months), and overall survival data were immature at that time. The study was open-label, and patients in the standard-of-care group could cross over to liso-cel if treatment failed. Only patients up to 75 years and eligible for transplantation were enrolled.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.